G protein coupled receptors (GPCRs) are essential for normal function of the central nervous system. Abnormalities in GPCR function may contribute to pathological states like schizophrenia, attention deficit disorder, bipolar disorder and drug addiction. This proposal aims to dissect the role of specific G protein signaling pathways in sensory perception, integration and gating. Engineered GPCRs developed by Dr. Bruce Conklin, the co-mentor on this proposal, fully activate Gi signaling in response to a synthetic ligand, but are insensitive to endogenous peptides and neurotransmitters. These RASSLs (receptors activated solely by synthetic ligands) have been expressed in specific brain regions of mice. RASSLs act as switches that activate the Gi signaling pathway in a specific neural circuit when triggered by drug administration. RASSLs will be used to activate Gi signaling in selected neural circuits of transgenic mice to reveal the contribution of this signaling pathway to olfactory behavior, and the abnormal sensory gating involved in psychoses and schizophrenia. Specific Aim 1 tests the hypothesis that RASSL activation can selectively disrupt olfactory behavior. Aim 2 tests the hypothesis that an imbalance of Gi signaling can induce disturbances in sensorimotor gating, attention or activity similar to those seen in schizophrenic patients. Aim 3 tests the hypothesis that the RASSL-mediated changes in behavior observed in Aims 1 and 2 correlate with markers of neural activity in specific circuits. The candidate, a Ph.D. neurobiologist, has leaned how to use RASSLs, both in vitro and in vivo, during 3.5 years of post-doctoral training with Dr. Conklin. Since this project requires sophisticated morphological, biochemical and behavioral analysis of transgenic mouse models, the candidate has joined the laboratory of Dr. Lennart Mucke, the primary sponsor of this project. Dr. Mucke's experience analyzing mouse models of human neuropsychiatric disease will contribute to the successful completion of this project. The mentoring and training received during this project will help the candidate achieve her career goal of an independent faculty research position.